Abstract
Glucocorticoid receptor is a transcription factor that is ubiquitously expressed. Glucocorticoids are circadian steroids that regulate a wide range of bodily functions, including immunity. Here we report that synthetic glucocorticoids affect 1035 mRNAs in isolated healthy human blood monocytes but only 165 in the respective six day-old monocyte-derived macrophages. The majority of the glucocorticoid response in monocytes concerns genes that are dynamic upon monocyte to macrophage differentiation, whereby macrophage-like mRNA levels are often reached in monocytes within four hours of treatment. Concomitantly, over 5000 chromosomal H3K27ac regions undergo remodelling, of which 60% involve increased H3K27ac signal. We find that chromosomal glucocorticoid receptor binding sites correlate with positive but not with negative local epigenomic effects. To investigate further we assigned our data to topologically associating domains (TADs). This shows that about 10% of macrophage TADs harbour at least one GR binding site and that half of all the glucocorticoid-induced H3K27ac regions are confined to these TADs. Our analyses are therefore consistent with the notion that TADs naturally accommodate information from sets of distal glucocorticoid response elements.
Highlights
Glucocorticoids are essential circadian steroid hormones that regulate peri-natal development[1], emotion processing and memory[2,3] the immune system[4] and metabolism[5,6]
GR tethering to DNA by another DNA-bound transcription factor, as demonstrated by STAT3-dependent GR occupancy of sites lacking a canonical GR binding site, has been shown to correlate with a small number of glucocorticoid hormone-dependent transcription repression events in a mouse pituitary cell line[37], and such mechanisms have been proposed for NFKB and AP-1 too as reviewed by Clark and Belvisi[32]
Glucocorticoid-induced monocyte and macrophage transcriptome responses differ in magnitude
Summary
Glucocorticoids are essential circadian steroid hormones that regulate peri-natal development[1], emotion processing and memory[2,3] the immune system[4] and metabolism[5,6]. A recent cellular and proteomic study reported that dexamethasone enhances Mo differentiation into Mf that can support erythropoiesis in vitro by phagocytosing extruded proerythrocyte nuclei[15] This indicates that healthy human circulating blood Mo are physiologically relevant glucocorticoid target cells. GR tethering to DNA by another DNA-bound transcription factor, as demonstrated by STAT3-dependent GR occupancy of sites lacking a canonical GR binding site, has been shown to correlate with a small number of glucocorticoid hormone-dependent transcription repression events in a mouse pituitary cell line[37], and such mechanisms have been proposed for NFKB and AP-1 too as reviewed by Clark and Belvisi[32]. Our results are consistent with the notion that TADs naturally integrate transcription regulation by distant cis-acting elements
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